Metabolism of flavonolignans in human hepatocytes

0489013 - MBÚ 2019 RIV NL eng J - Článek v odborném periodiku
Vrba, J. - Papoušková, B. - Roubalová, L. - Zatloukalová, M. - Biedermann, David - Křen, Vladimír - Valentová, Kateřina - Ulrichová, J. - Vacek, J.
Metabolism of flavonolignans in human hepatocytes.
Journal of Pharmaceutical and Biomedical Analysis. Roč. 152, APR 15 2018 (2018), s. 94-101. ISSN 0731-7085. E-ISSN 1873-264X
Grant CEP: GA ČR(CZ) GA15-03037S
Institucionální podpora: RVO:61388971
Klíčová slova: Silybin * Silymarin * Cytochrome P450
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 2.983, rok: 2018

This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry. We found that each of the tested compounds was metabolized in vitro by one or more CYP enzymes, which catalyzed O-demethylation, hydroxylation, hydrogenation and dehydrogenation reactions. In human hepatocytes, silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, and isosilybins A and B were directly conjugated by sulfation or glucuronidation. Moreover, isosilybin A was also converted to a methyl derivative, while isosilybin B was hydroxylated and methylated. Silydianin and 2,3-dehydrosilydianin were found to undergo hydrogenation and/or glucuronidation. In addition, 2,3-dehydrosilydianin was found to be metabolically the least stable flavonolignan in human hepatocytes, and its main metabolite was a cleavage product corresponding to a loss of CO. We conclude that the hepatic biotransformation of flavonolignans primarily involves the phase II conjugation reactions, however in some cases the phase I reactions may also occur. These results are highly relevant for research focused on flavonolignan metabolism and pharmacology.
Trvalý link: http://hdl.handle.net/11104/0283502